Imidazole n-benzyldioxol derivatives, method for preparing same, resulting intermediates, pharmaceutical compositions and use of said derivatives as endothelin antagonists

ABSTRACT

PCT No. PCT/FR96/01749 Sec. 371 Date Jun. 9, 1998 Sec. 102(e) Date Jun. 9, 1998 PCT Filed Nov. 7, 1996 PCT Pub. No. WO97/17339 PCT Pub. Date May 15, 1997The invention relates to the new products of formula (I): in which: R1 represents alkyl, optionally substituted or cycloalkyl optionally interrupted by heteroatoms, R2; R3 both represent or carry an acid function or an acid isosteric function, and Y represents phenyl substituted in particular by a dioxol radical, these products being in all the isomeric forms and the salts, as medicaments.

This application is a 371 of PCT FR96/01749 filed Nov. 7, 1996.

The present invention relates to new derivatives of imidazoleN-benzyldioxole, their preparation process, the new intermediatesobtained, their use as medicaments, the pharmaceutical compositionscontaining them and the new use of such derivatives of imidazole.

A subject of the present invention is the products of formula (I):##STR2## in which: R₁ represents an alkyl radical, optionallysubstituted by one or more hydroxyl or alkoxy radicals, the alkyl andalkoxy radicals being linear or branched and containing at most 6 carbonatoms, or a saturated or unsaturated cyclic radical constituted by 3 to7 members, and optionally containing one or more identical or differentheteroatoms chosen from oxygen, sulphur and nitrogen atoms,

R₂ and R₃, identical or different, both represent or carry an acidfunction or an acid isosteric function and Y represents the phenylradical substituted by a dioxol radical and optionally substituted byanother substituent chosen from halogen atoms and alkoxy and alkylradicals containing at most 4 carbon atoms,

said products of formula (I) being in all possible racemic, enantiomericand diastereoisomeric isomer forms, as well as the addition salts withmineral and organic acids or with mineral and organic bases of saidproducts of formula (I).

In the products of formula (I) and in what follows:

the term linear or branched alkyl radical designates the followingradicals: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl,nonyl and decyl as well as their linear or branched position isomers,

the term linear or branched alkoxy radical designates the followingradicals: methoxy, ethoxy, propoxy, isopropoxy, linear, secondary ortertiary butoxy, pentoxy or hexoxy as well as their linear or branchedposition isomers,

the term halogen atom preferably designates the chlorine atom, but canalso represent a fluorine, bromine or iodine atom,

the term saturated or unsaturated cyclic radical constituted by 3 to 7members and optionally containing one or more identical or differentheteroatoms, chosen from oxygen, sulphur or nitrogen atoms designates onthe one hand a cycloalkyl radical such as for example the cyclopropyl,cyclobutyl radicals and quite particularly the cyclopentyl andcyclohexyl radicals or a carbocyclic radical interrupted by one or moreheteroatoms chosen from oxygen, nitrogen or sulphur atoms such as quiteparticularly the dioxolane, dioxane, dithiolane, thiooxolane orthiooxane radical, on the other hand the phenyl, thienyl, furyl, pyridylor tetrazolyl radicals,

the term acid function or acid isosteric function designates the free,salified or esterified carboxy radical, the free or salified tetrazolylradical, or the following radicals:

SO₃ H, --PO(OH)₂,

NHSO₂ --CF₃

NH--SO₂ --NH--V

NH--SO₂ --NH--CO--V

NH--CO--V

NH--CO--NH--V

NH--CO--NH--SO₂ --V

SO₂ --NH--V

SO₂ --NH--CO--V

SO₂ --NH--CO--NH--V

CONH--V

CO--NH--OH

CONH--SO₂ --V

in which V represents a linear or branched alkyl or alkenyl radicalcontaining at most 6 carbon atoms or a phenyl, pyridyl, pyrimidinyl,piperazinyl, thienyl or tetrazolyl radical, the alkyl, alkenyl andphenyl radicals being optionally substituted by one or more radicalschosen from halogen atoms and hydroxy, alkoxy or phenyl radicals, allthe phenyl radicals and the piperazinyl radical being optionallysubstituted by a linear or branched alkyl radical containing at most 4carbon atoms.

The carboxy radical or radicals of the products of formula (I) can besalified or esterified by various groups known to a man skilled in theart amongst which there can be mentioned, for example:

among the salification compounds, mineral bases such as, for example, anequivalent of sodium, potassium, lithium, calcium, magnesium or ammoniumor organic bases such as, for example, methylamine, propylamine,trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine,tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline,dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine,histidine, N-methylglucamine,

among the esterification compounds, the alkyl radicals to form alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals beingable to be substituted by radicals chosen for example from halogenatoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or arylradicals such as, for example, in the following groups: chloromethyl,hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl,dimethylaminoethyl, benzyl or phenethyl.

The addition salts with mineral or organic acids of the products offormula (I) can be, for example, the salts formed with the followingacids: hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric,phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric,succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic,alkylmonosulphonic such as for example methanesulphonic,ethanesulphonic, propanesulphonic, alkyldisulphonic such as for examplemethanedisulphonic, alpha, beta-ethanedisulphonic, arylmonosulphonicsuch as benzenesulphonic and aryldisulphonic.

It should be remembered that stereoisomerism can be defined in itsbroadest sense as the isomerism of compounds having the same developedformulae, but whose various groups are arranged differently in space,such as in particular in the boat and chair shapes of cyclohexane andmonosubstituted cyclohexanes whose substituent can be in axial orequatorial position, and the different possible rotational conformationsof ethane derivatives. However, another type of stereoisomerism exists,due to the different spatial arrangements of fixed substituents, eitheron double bonds, or on rings, which is often called geometricalisomerism or cis-trans isomerism. The term stereoisomeric is used in thepresent Application in its broadest sense and therefore relates to allof the compounds indicated above.

Therefore a subject of the present invention is the products of formula(I) as defined above in which: R₁ and Y have the meanings indicatedabove, and R₂ and R₃, identical or different, represent or carry a free,salified or esterified carboxy radical or a free or salified tetrazolylradical, said products of formula (I) being in all possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with mineral and organic acids or with mineral and organic basesof said products of formula (I).

A particular subject of the present invention is the products of formula(I) as defined above, in which: R₁ represents an alkyl radical,optionally substituted by one or more hydroxyl or alkoxy radicals, thealkyl and alkoxy radicals being linear or branched and containing atmost 6 carbon atoms, a cycloalkyl radical containing 3 to 6 members andoptionally containing one or two oxygen, nitrogen or sulphur atoms, athienyl or furyl radical, R₂ represents a --(CH₂)_(n) --S--A radical, inwhich n represents an integer from 0 to 4, S represents a sulphur atomand A represents:

either a linear or branched alkyl radical, containing at most 10 carbonatoms and substituted by a free, salified or esterified carboxy radicalor by a free or salified tetrazolyl radical, or a cycloalkyl radicalconstituted by 5 or 6 members, optionally containing one or two oxygenor nitrogen atoms and substituted by a free, salified or esterifiedcarboxy radical, by a free or salified tetrazolyl radical, or by alinear or branched alkyl, alkenyl, alkoxy or alkylthio radicalcontaining at most 6 carbon atoms optionally interrupted by an oxygen orsulphur atom, and

themselves substituted by a free, salified or esterified carboxy radicalor by a free or salified tetrazolyl radical, R₃ represents a free,salified or esterified carboxy radical or a free or salified tetarazolylradical, and Y has the meaning indicated above,

said products of formula (I) being in all possible racemic, enantiomericand diastereoisomeric isomer forms, as well as the addition salts withmineral and organic acids or with mineral and organic bases of saidproducts of formula (I).

In the products of formula (I) and in what follows:

the term linear or branched alkenyl radical designates vinyl, allyl,1-propenyl, butenyl, 1-butenyl, pentenyl or hexenyl radicals as well astheir linear or branched position isomers,

the term alkylthio radical designates radicals in which the alkylradical is as defined above such as for example in methylthio,ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio,tert-butylthio, isopentylthio, isohexylthio, but also heptylthio,octylthio, nonylthio or decylthio as well as their linear or branchedposition isomers.

Among the alkyl, alkenyl, alkoxy or alkylthio radicals interrupted byone or more heteroatoms, there can be mentioned for example thefollowing radicals: methoxymethyl, methoxyethoxymethyl,propylthiopropyl, propyloxypropyl, propylthioethyl, methylthiomethyl, aswell as these same radicals in which the alkyl radicals such as methyl,ethyl or propyl are replaced by alkenyl, alkoxy or alkylthio radicals asdefined above to give for example the following radicals: methoxyvinyl,methoxyallyl, methoxymethoxy, methoxyethoxy, methoxymethylthio,methoxyethylthio, ethoxypropylthio, ethylthiopropoxy, propylthiomethoxyor also ethylthioethoxy.

A more particular subject of the present invention is the products offormula (I) as defined above, in which R₁, represents one of thefollowing radicals: methoxymethyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, terbutyl, cyclopentyl, cyclohexyl, dioxolane, dioxane,dithiolane, thienyl or furyl,

R₂ represents either an alkylthio radical containing 3 to 10 carbonatoms substituted by a free, salified or esterified carboxy radical orby a free or salified tetrazolyl radical, or a cyclohexylthio,cyclopentylthio or piperidinylthio radical substituted by a free,salified or esterified carboxy radical; by a free or salified tetrazolylradical; or by an alkyl, alkenyl, alkoxy or alkylthio radical containingat most 4 carbon atoms themselves substituted by a free, salified oresterified carboxy radical or by a free or salified tetrazolyl radical,

R₃ represents a free, salified or esterified carboxy radical or a freeor salified tetrazolyl radical, and Y represents a phenyl radicalsubstituted by a dioxol radical and optionally substituted by a halogenatom, said products of formula (I) being in all possible racemic,enantiomeric and diastereoisomeric isomer forms, as well as the additionsalts with mineral and organic acids or with mineral and organic basesof said products of formula (I).

An even more particular subject of the invention is the products offormula (I) as defined above, in which R₁ represents a methoxymethyl,n-propyl, isopropyl, n-butyl, isobutyl, terbutyl and dioxolane radical,

R₂ represents either a linear or branched alkylthio radical containing3, 4 or 5 carbon atoms, substituted by a free, salified or esterifiedcarboxy radical or the cyclohexylthio radical substituted by a free,salified or esterified carboxy radical, or by an alkyl or alkenylradical containing at most 4 carbon atoms, themselves substituted by afree, salified or esterified carboxy radical,

R₃ represents a free, esterified or salified carboxy radical,

Y represents a phenyl radical substituted by a dioxol radical and by ahalogen atom, said products of formula (I) being in all possibleracemic, enantiomeric and diastereoisomeric isomer forms, as well as theaddition salts with mineral and organic acids or with mineral andorganic bases of said products of formula (I).

A quite particular subject of the present invention is the products offormula (I) as defined above, corresponding to the following formulae:

4-((4-(carboxymethylene) cyclohexyl)thio)-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2-propyl-1H-imidazole-5-carboxylic acid,

4-((5-carboxypentyl) thio)-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2-(1,3-dioxolan-2-yl)-1H-imidazole-5-carboxylic acid,

4-((4-(carboxymethyl) cyclohexyl)thio)-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2-propyl-1H-imidazole-5-carboxylic acid,

1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 4-((4-carboxy-cyclohexyl)thio) 2-propyl 1H-imidazole 5-carboxylic acid,

4-(((4-carboxycyclohexyl) methyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole 5-carboxylic acid,

cis 4-(((2-((carboxymethoxy) methyl) cyclohexyl) methyl) thio)1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole5-carboxylic acid,

trans 4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-(1,3-dioxolan-2-yl) 1H-imidazole5-carboxylic acid,

4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-(2-furanyl) 1H-imidazole 5-carboxylicacid,

trans 4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-cyclopentyl 1H-imidazole 5-carboxylicacid,

trans 3-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-(2-thienyl) 1H-imidazole 5-carboxylicacid,

4-((4-carboxycyclohexyl) thio) 1-((6-chloro 1,3-benzodioxol-5-yl)methyl) 2-(2-furanyl) 1H-imidazole 5-carboxylic acid,

disodium salt of 4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole 5-carboxylic acid,

dipotassium salt of 4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole 5-carboxylic acid.

Also a subject of the present invention is the preparation process forthe products of formula (I), as defined above, characterized in that:either a compound of formula (II): ##STR3## in which R'₁ has the meaningindicated above for R₁, in which the optional reactive functions areoptionally protected by protective groups, is subjected to a reactionwith a compound of formula (III): ##STR4## in which Hal represents ahalogen atom, and Y' has the meaning indicated above for Y, in which theoptional reactive functions are optionally protected by protectivegroups, in order to obtain the product of formula (IV): ##STR5## inwhich R'₁ and Y' have the meanings indicated above, which product offormula (IV) can be subjected to a halogenation reaction, in order toobtain the product of formula (V): ##STR6## in which R'₁, Hal and Y'have the meanings indicated above, or a compound of formula (VI):##STR7## in which Hal has the meaning indicated above, is subjectedeither to a reaction with the compound of formula (III) as definedabove, or to the action of a protective group P, in order to obtain aproduct of formula (VII): ##STR8## in which Hal has the meaningindicated above and W represents either --CH₂ --Y' with Y' as definedabove, or P which represents a protective group of the nitrogen atom,which product of formula (VII) is subjected to a halogen-metal exchangereaction then to a reaction with dimethylformamide or with anelectrophile of formula (VIII_(a)) or (VIII_(b)):

    L.sub.1 L--CHO                                             (VIII.sub.a)

    L.sub.1 --CO--Cl                                           (VIII.sub.b)

in which L₁ represents a linear or branched alkyl radical containing atmost 6 carbon atoms and optionally substituted by a protected alkoxyl orhydroxy radical, in order to obtain a product of formula (IX): ##STR9##in which Hal and W have the meanings indicated above, R"₁ represents analkyl-carbonyl, formyl or hydroxyalkyl radical in which the alkylradical has the meaning indicated above and in which the optionalreactive functions are optionally protected by protective groups, whichproducts of formulae (V) and (IX) can be subjected to a halogen-metalexchange reaction on one of the halogen atoms then to a reaction withCO₂ or DMF or an electrophilic compound of formula (X): ##STR10## inwhich alk represents an alkyl radical containing at most 4 carbon atoms,in order to obtain the compound of formula (XI): ##STR11## in which R'"₁represents R'₁ or R"₁ as defined above, Hal and W have the meaningsindicated above and Z₃ represents the free or esterified carboxy radicalor the formyl radical, which compound of formula (XI) can be subjectedto a reaction with a compound of formula (XII):

    A'--S--M                                                   (XII)

in which S represents a sulphur atom, M represents a metal such assodium, potassium or copper and A' represents A as defined above, inwhich the optional reactive functions are optionally protected byprotective groups in order to obtain the compound of formula (XIII):##STR12## in which R'"₁, Y', A', Z₃ and W have the meanings indicatedabove, which product of formula (XIII) when Z₃ represents the formylradical, can be subjected to an oxidation reaction in order to obtainthe product of formula (XIV): ##STR13## in which R'"₁, A' and W have themeanings indicated above, and Z₄ represents the cyano radical or thecarboxy radical free or esterified by a linear or branched alkyl radicalcontaining at most 6 carbon atoms, which products of formula (XIII) or(XIV), in the case where W represents P as defined above and afterrelease of the amine function blocked by P as defined above, are reactedwith the compound of formula (III) as defined above, in order to obtaina product of formula (XV): ##STR14## in which R'"₁, A' and Y' have themeanings indicated above, and R"₃ represents Z₃ or Z₄ as defined above,or a compound of formula (XVI): ##STR15## in which R'₁ has the meaningindicated above and R'₂ and R'₃ have the meanings indicated above for R₂and R₃ respectively in which the optional reactive functions areoptionally protected by protective groups, is subjected to a reactionwith the compound of formula (III) as defined above, in order to obtaina product of formula (I₁): ##STR16## in which R'₁, R'₂, R'₃ and Y' havethe definitions indicated above, or a compound of formula (XVII):##STR17## in which R'₁ has the meaning indicated previously, issubjected to a hydrolysis reaction in order to obtain the product offormula (XVIII): ##STR18## in which R'₁ has the meaning indicatedpreviously and one or both of Z₅ and Z₆ represents a free or esterifiedcarboxy radical and if appropriate, the other one of Z₅ and Z₆ retainingthe CN value, which product of formula (XVIII) is reacted with thecompound of formula (III) as defined above in order to obtain theproduct of formula (XIX): ##STR19## in which R'₁, Y', Z₅ and Z₆ have themeanings indicated previously, or a compound of formula (XX):

    Y'--CHO                                                    (XX)

in which Y' has the meaning indicated above, is subjected to a compoundof formula (XXI): ##STR20## in order to obtain, after reduction of theintermediate imine, a product of formula (XXII): ##STR21## in which Y'has the meaning indicated above, which is subjected to a compound offormula (XXIII): ##STR22## in which R'₁ has the meaning indicated above,in order to obtain the product of formula (XXIV): ##STR23## in which Y'and R'₁ have the meanings indicated above, which is subjected to acompound of formula (XXV):

    A'--S--H                                                   (XXV)

in which A' has the meaning indicated above, in order to obtain theproduct of formula (XXVI): ##STR24## in which Y', R'₁ and A' have themeanings indicated above, which is cyclized into the product of formula(I₂): ##STR25## in which Y', R'₁ and A' have the meanings indicatedabove, or a compound of formula (XXI): ##STR26## is subjected to theaction of a compound of formula (XXIII): ##STR27## in which R'₁ has themeaning indicated above in order to obtain a compound of formula(XXIVa): ##STR28## in which R'₁, has the meaning indicated above, whichis subjected to the action of a compound of formula (XXV):

    A'--S--H                                                   (XXV)

in which A' has the meaning indicated above in order to obtain a productof formula (XXVIa): ##STR29## in which R'₁ and A' have the meaningsindicated previously, which is cyclized into the product of formula(XXVIb): ##STR30## in which R' and A' have the meaning indicatedpreviously, which is subjected to the action of a product of formula(III): ##STR31## in which Hal and Y' have the meaning indicated above inorder to obtain a product of formula (I₂) as defined above, whichproducts of formulae (IX), (XI), (XIII), (XIV), (XV), (XIX), (I₁) and(I₂) can be products of formula (I) and which, in order to obtainproducts or other products of formula (I), can be subjected, if desiredand if necessary, to one or more of the following conversion reactions,in any order:

a) an esterification reaction of the acid function,

b) a saponification reaction of the ester function into an acidfunction,

c) a conversion reaction of the ester function into a formyl function,

d) a conversion reaction of the cyano function into an acid function,

e) an oxidation reaction of the alkylthio group into a correspondingsulphoxide or sulphone,

f) a reduction reaction of the free or esterified carboky function to analcohol function,

g) a conversion reaction of the alkoxy function into a hydroxylfunction, or also of the hydroxyl function into an alkoxy function,

h) an oxidation reaction of the alcohol function into an aldehyde, acidor ketone function,

i) a conversion reaction of the formyl radical into a carbamoyl radical,

j) a conversion reaction of the carbamoyl radical into a nitrileradical,

k) a conversion reaction of the nitrile radical into a tetrazolylradical,

l) a conversion reaction of a halogenated function into a formyl oresterified carboxy function,

m) a conversion reaction of a formyl radical into a CH₂ --CO₂ alk orCH═CH--CO₂ alk function in which alk represents an alkyl radicalcontaining 1 to 4 carbon atoms, then if appropriate, conversion into thecorresponding acid,

n) a conversion reaction of a formyl radical into a --CH═CH--A' radicalthen if appropriate into a --CH₂ --CH₂ A' radical,

o) an oxidation reaction of the S-alk radical into ##STR32## thenconversion into an SH function and if appropriate into S-A' in which alkand A' have the meaning indicated previously,

p) a reaction to eliminate the protective groups which can be carried bythe protected reactive functions,

q) a salification reaction by a mineral or organic acid or by a base inorder to obtain the corresponding salt,

r) a resolution reaction of the racemic forms into resolved products,said products of formula (I) thus obtained being in all possibleracemic, enantiomeric and diastereoisomeric isomer forms.

It can be noted that such conversion reactions of substituents intoother substituents can also be carried out on the starting products aswell as on the intermediate products as defined above before continuingthe synthesis according to the reactions indicated in the processdescribed above.

Under preferred conditions for implementing the invention, the processdescribed above can be carried out in the following manner:

In the product of formula (III), the halogen atom preferably representsa bromine atom but can also represent a chlorine or iodine atom. Thecondensation reaction of the imidazoles of formulae (II), (VI), (XVI),(XIII) and (XIV) as defined above (in the case of the products offormulae (XIII) and (XIV), when w represents P and after deprotection ofthe nitrogen atom), with the compound of formula (III) as defined above,in order to obtain respectively the products of formulae (IV), (VII)when W represents Y', (XV) and (I₁) as defined above, can be carried outin a solvent such as for example dimethylformamide or alsodimethylacetamide, tetrahydrofuran, dimethoxyethane ordimethylsulphoxide under reflux of the solvent or at ambienttemperature, preferably under agitation; the reaction is preferablycarried out in the presence of a base such as for example sodium orpotassium hydride or also sodium or potassium carbonate, sodium orpotassium methylate or ethylate or tert-butylate. The halogenationreaction of the compound of formula (IV) as defined above into acompound of formula (V) as defined above, can be carried out under theusual conditions known to a man skilled in the art and in particular bybromination using NBS in CH₂ Cl₂ or also Br₂ in acetic acid.

The compounds of formulae (V), (VII) and (IX) as defined above can besubjected to a halogen-metal exchange reaction on the halogen atom byreaction with an organo-metallic compound such as nBuli or ethylmagnesium bromide in a solvent such as tetrahydrofuran at a temperatureof approximately -78° C. for Buli and ambient temperature for ethylmagnesium bromide.

The carboxylation reaction using CO₂ and the formylation reaction usingdimethylformamide of the compounds of formulae (V) or (IX) into thecompound of formula (XI) can be carried out according to the usualconditions known to a man skilled in the art namely for example intetrahydrofuran at ambient temperature.

L₁ represents an alkyl radical such that R₁ " represents thecorresponding values chosen from values of R₁ as defined above in whichthe optional reactive functions are optionally protected by protectivegroups.

The reaction of the compound of formula (V) or (IX) as defined abovewith the compound of formula (X), as defined above, in order to obtainthe corresponding compound of respective formula (XI) as defined abovecan be carried out in an identical manner by using ethyl magnesiumbromide as metallation agent in tetrahydrofuran at ambient temperature.

The reaction of the compound of formula (VII) with the compounds offormula (VIII_(a)) or (VIII_(b)) can be carried out according to theusual conditions known to a man skilled in the art namely for example intetrahydrofuran at ambient temperature.

The amine function of the compounds of formulae (XIII) and (XIV) asdefined above, protected by P as defined above, can be released underthe usual conditions known to a man skilled in the art and in particularwhen P represents the --CH₂ --O--(CH₂)₂ --Si(CH₃)₃ radical, the hydrogenatom can be released in trifluoroacetic acid or also in the presence ofa fluoride ion.

The saponification reaction can be carried out according to the usualmethods known to a man skilled in the art, such as for example in asolvent such as methanol or ethanol, dioxane or dimethoxyethane, in thepresence of soda or potash or also caesium carbonate.

The reduction or oxidation reactions of the product of formula (XIII)into the product of formula (XIV) can be carried out according to theusual methods known to a man skilled in the art.

In the reactions described above, the operation can be carried out inthe following manner:

the reaction of the compound of formula (XX) with the compound offormula (XXI) to obtain the compound of formula (XXII) can be carriedout in a solvent such as for example methylene chloride in the presenceof an acid catalyst such as for example amberlist then by reduction forexample with sodium borohydride in acetic acid and methylene chloride,

the reaction of the compound of formula (XXII) or (XXI) with thecompound of formula (XXIII) to obtain respectively the compound offormula (XXIV) or (XXIVa) can be carried out in a solvent such as forexample tetrahydrofuran or methylene chloride, in the presence of a basesuch as pyridine or also triethylamine or sodium or potassium carbonate,

the reaction of the compound of formula (XXIV) or (XXIVa) with thecompound of formula (XXV) to obtain respectively the compound of formula(XXVI) or (XXVIa) can be carried out in an alcohol such as methanol orethanol in the presence of a base such as triethylamine or pyridine.

the cyclization of the compound of formula (XXVI) or (XXVI_(a))respectively into the product of formula (I₂) or (XXVI_(b)) can becarried out in the presence of an anhydride such as for example propanephosphonic anhydride in ethyl acetate.

the reaction of the compound of formula (XXVIa) with the compound offormula (III) can be carried out in an identical manner to thatindicated above for the condensation reaction of the product of formula(III) and the imidazoles of formulae (II), (VI), (XVI), (XIII) and(XIV).

According to the values of R'₁, R"₁, R'"₁, R'₂, R'₃, R"₃, the productsof formulae (IX), (XI), (XIII), (XIV), (XV), (XIX), (I₁) and (I₂)constitute or do not constitute products of formula (I) and can giveproducts of formula (I), or be converted into other products of formula(I) by being subjected to one or more of reactions a) to r) indicatedabove.

Thus the various reactive functions which can be carried by some of thecompounds of the reactions defined above can, if necessary, beprotected: they are for example the hydroxyl, acyl, free carboxyradicals or also the amino and monoalkylamino radicals which can beprotected by the appropriate protective groups.

The following non-exhaustive list of examples of the protection of thereactive functions can be mentioned:

the hydroxyl groups can be protected for example by alkyl radicals suchas tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl,tetrahydropyrannyl, benzyl or acetyl,

the amino groups can be protected for example by acetyl, trityl, benzyl,tert-butoxycarbonyl, phthalimido radicals or other radicals known in thechemistry of the peptides,

the acyl groups such as the formyl group can be protected for example inthe form of cyclic or non-cyclic ketals or thioketals such as dimethylor diethylketal or ethylene dioxyketal, or diethylthioketal orethylenedithioketal,

the acid functions of the products described above can be, if desired,amidified by a primary or secondary amine for example in methylenechloride in the presence, for example, of1-ethyl-3-(dimethylaminopropyl) carbodiimide hydrochloride at ambienttemperature:

the acid functions can be protected for example in the form of estersformed with easily cleavable esters such as benzyl or terbutyl esters oresters known in the chemistry of the peptides.

The reactions to which the products of formulae (IX), (XI), (XIII),(XIV), (XV), (XIX), (I₁) and (I₂) as defined above can be subjected, ifdesired or if necessary, can be carried out, for example, as indicatedhereafter:

a) The products described above can, if desired, be subjected toesterification reactions on the optional carboxy functions, which can becarried out according to the usual methods known to a man skilled in theart.

b) The optional conversions of the ester functions into an acid functionof the products described above can be, if desired, carried out underthe usual conditions known to a man skilled in the art in particular byacid or alkaline hydrolysis for example by soda or potash in analcoholic medium such as, for example, in methanol or also byhydrochloric or sulphuric acid.

c) The conversion reaction of the ester function ##STR33## in which E₁can represent an optionally substituted and optionally protected alkylradical, into a formyl radical can be carried out as is described in theexperimental part, or according to the usual methods known to a manskilled in the art, in particular by saponification of the ester into anacid, then converted into the acid chloride for example by the action ofthionyl chloride, and then reduced for example by hydrogenation onpalladium.

d) The optional cyano functions of the products described above can be,if desired, converted into an acid function under the usual conditionsknown to a man skilled in the art for example by a double hydrolysiscarried out in an acid medium such as for example in a sulphuric acid,glacial acetic acid and water mixture, these three compounds preferablybeing in equal proportions, or also in a soda, ethanol and water mixtureunder reflux.

e) The optional alkylthio groups of the products described above can be,if desired, converted into the corresponding sulphoxide or sulphonefunctions under the usual conditions known to a man skilled in the artsuch as for example by peracids such as for example peracetic acid ormetachloro-perbenzoic acid or also by ozone, oxone, sodium periodate ina solvent such as for example methylene chloride or dioxane at ambienttemperature.

The obtaining of the sulphoxide function can be encouraged by anequimolar mixture of the product containing an alkylthio group and areagent such as in particular a peracid.

The obtaining of the sulphone function can be encouraged by a mixture ofthe product containing an alkylthio group with an excess of reagent suchas in particular a peracid.

f) The optional free or esterified carboxy functions of the productsdescribed above can be, if desired, reduced to an alcohol function bythe methods known to a man skilled in the art: the optional esterifiedcarboxy functions can be, if desired, reduced to an alcohol function bythe methods known to a man skilled in the art and in particular bylithium and aluminium hydride in a solvent such as for exampletetrahydrofuran or also dioxane or ethyl ether.

The optional free carboxy functions of the products described above canbe, if desired, reduced to an alcohol function in particular by boronhydride.

g) The optional alkoxy functions such as in particular methoxy of theproducts described above can be, if desired, converted into a hydroxylfunction under the usual conditions known to a man skilled in the artfor example by boron tribromide in a solvent such as for examplemethylene chloride, by pyridine hydrobromide or hydrochloride or also byhydrobromic of hydrochloric acid in water or trifluoroacetic acid underreflux.

h) The optional alcohol functions of the products described above canbe, if desired, converted into an aldehyde or acid function by oxidationunder the usual conditions known to a man skilled in the art such as forexample by the action of manganese oxide in order to obtain aldehydes orof Jones reagent in order to produce acids.

i) j) The conversion reactions of the formyl radical into a carbamoylradical and of the carbamoyl radical into a nitrile radical, are inparticular carried out for R₃ and R₄ according to the usual conditionsknown to a man skilled in the art, such as for example passage via theketo nitrile and displacement by an amine (Chem. Comm. 1971, p.733).

k) The optional nitrile functions of the products described above canbe, if desired, converted into tetrazolyl under the usual conditionsknown to a man skilled in the art such as for example by thecycloaddition of a metal azide such as for example sodium azide or atrialkyltin azide on the nitrile function as indicated in the methoddescribed in the article referenced as follows:

J. Organometallic Chemistry., 33, 337 (1971) KOZIMA S. et al.

It can be noted that the conversion reaction of a carbamate into ureaand in particular of a sulphonylcarbamate into sulphonylurea, can becarried out for example under reflux of a solvent such as for exampletoluene in the presence of the appropriate amine.

l) The conversion of a halogenated radical into a formyl radical can inparticular be carried out by the action of an organo-metallicderivative, for example ethyl magnesium bromide, in an organic solvent,

m) the conversion of the formyl radical into a CH═CH--CO₂ alk radicalcan be carried out by a Wittig-type reaction by condensation of anappropriate phosphonium salt in the presence of sodium hydride; theconversion into an acid is carried out by hydrolysis, for example usinga base such as soda in an alcoholic medium,

n) the conversion of the formyl radical into a --CH═CH--A' radical canbe carried out by a Wittig reaction as indicated above; the conversioninto the --CH₂ --CH₂ --A' radical is carried out by reduction, usinghydrogen in the presence of a catalyst, for example platinum oxide.

It can be noted that the conversion of the formyl radical into a CH₂ OHradical can be carried out using a reducing agent, for example sodiumborohydride in ethanol at ambient temperature; the conversion into the--CH₂ --SR radical can be carried out by the action of the appropriateR-SH thiol on the intermediate mesylate prepared beforehand by theaction of mesyl chloride on alcohol in the presence of Hunig base,

o) the oxidation of the S-alk substituent into the sulphoxide can becarried out for example, by the action of metachloroperbenzoic acid; theconversion of the thiol is obtained by the PUMMERER reaction for examplein the presence of trifluoroacetic anhydride; the conversion of the SHsubstituent into SZ₂ can be obtained by the action of a halogenatedderivative Hal-Z₂ for example iodocyclohexane.

It is understood that the reactions described above can be carried outaccording to the usual methods known to a man skilled in the art.

p) The elimination of the protective groups such as for example thoseindicated above can be carried out under the usual conditions known to aman skilled in the art in particular by an acid hydrolysis carried outwith an acid such as hydrochloric, benzene sulphonic or paratoluenesulphonic, formic or trifluoroacetic acid or also by catalytichydrogenation.

The phthalimido group can be eliminated by hydrazine.

A list of the different protective group which can be used will be foundfor example in the Patent BF 2,499,995.

q) The products described above can, if desired, be subjected tosalification reactions for example by a mineral or organic acid or by amineral or organic base according to the usual methods known to a manskilled in the art.

r) The optional optically-active forms of the products described abovecan be prepared by resolution of the racemics according to the usualmethods known to a man skilled in the art.

Illustrations of such reactions defined above are given in thepreparation of the examples described hereafter.

The compounds of formula (I) as defined above as well as their additionsalts with acids have useful pharmacological properties.

The products of formula (I) as defined above, are endowed withantagonistic properties for the endothelin receptors and are thus inparticular inhibitors of the effects of endothelin, in particular thevaso-constrictive and hypertensive effects induced by endothelin. Inparticular an anti-ischemic effect can be noted, the vasoconstrictiveactivity of endothelin being eliminated.

The products of formula (I) are also capable of opposing the stimulatingeffects of endothelin at the level of all cell types, in particularsmooth muscle cells, fibroblasts, neuronal cells and bone cells.

These properties justify their use in therapeutics and a particularsubject of the invention is as medicaments, the products of formula (I),said products of formula (I) being in all possible racemic, enantiomericand diastereoisomeric isomer forms, as well as the addition salts withpharmaceutically acceptable mineral and organic acids or mineral andorganic bases of said products of formula (I).

Therefore a more particular subject of the invention is as medicaments,the products as defined by formula (I) above, in which R₁ represents amethoxymethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, terbutyl,cyclopentyl, cyclohexyl, dioxolane, dioxane, dithiolane, thienyl orfuryl radical,

R₂ represents either an alkylthio radical containing 3 to 10 carbonatoms substituted by a free, salified or esterified carboxy radical orby a free or salified tetrazolyl radical, or a cyclohexylthio,cyclopentylthio or piperidinylthio radical substituted by a free,salified or esterified carboxy radical; by a free or salified tetrazolylradical; or by an alkyl, alkenyl, alkoxy or alkylthio radical containingat most 4 carbon atoms themselves substituted by a free, salified oresterified carboxy radical or by a free or salified tetrazolyl radical,

R₃ represents a free, salified or esterified carboxy radical or a freeor salified tetrazolyl radical, and Y represents a phenyl radicalsubstituted by a dioxol radical and optionally substituted by a halogenatom, said products of formula (I) being in all possible racemic orptically active isomer forms, as well as the addition salts withpharmaceutically acceptable mineral and organic acids or mineral andorganic bases of said products of formula (I). A quite particularsubject of the invention is, as medicaments, the products describedhereafter in the examples and in particular the products of formula (I)as defined above, corresponding to the following formulae:

4-((4-(carboxymethylene) cyclohexyl)thio)-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2-propyl-1H-imidazole-5-carboxylic acid,

4-((5-carboxypentyl) thio)-1-((6-chloro-1,3-benzo-dioxol-5-yl)methyl)-2-(1,3-dioxolan-2-yl)-1H-imidazole-5-carboxylic acid,

4-((4-(carboxymethyl) cyclohexyl)thio)-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2-propyl-1H-imidazole-5-carboxylic acid,

1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 4-((4-carboxycyclohexyl)thio) 2-propyl 1H-imidazole 5-carboxylic acid,

4-(((4-carboxycyclohexyl) methyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole 5-carboxylic acid,

cis 4-(((2-((carboxymethoxy) methyl) cyclohexyl) methyl) thio)1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole5-carboxylic acid,

trans 4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-(1,3-dioxolan-2-yl) 1H-imidazole5-carboxylic acid,

4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-(2-furanyl) 1H-imidazole 5-carboxylicacid,

trans 4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-cyclopentyl 1H-imidazole 5-carboxylicacid,

trans 3-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-(2-thienyl) 1H-imidazole 5-carboxylicacid,

4-((4-carboxycyclohexyl) thio) 1-((6-chloro 1,3-benzodioxol-5-yl)methyl) 2-(2-furanyl) 1H-imidazole 5-carboxylic acid,

disodium salt of 4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole 5-carboxylic acid,

dipotassium salt of 4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole 5-carboxylic acid,as well as the addition salts with pharmaceutically acceptable mineralor organic acids or mineral and organic bases

The medicaments, which are a subject of the invention, can for examplebe used in the treatment of all vascular spasms, in the treatment ofvasospasm following a cerebral haemorrhage, in the treatment of coronaryspasms, peripheral vascular spasms as well as in the treatment of renalinsufficiencies. These medicaments can also be used in the treatment ofmyocardial infarction, congestive cardiac insufficiency, in theprevention of the recurrence of post-angioplastic stenosis, cardiac andvascular fibroses, in the treatment of atherosclerosis, certain forms ofhypertension such as in particular pulmonary hypertension, as well as inthe treatment of asthma.

The medicaments, which are a subject of the invention, can also be usedin the treatment of osteoporosis, prostatic hyperplasia and as neuronalprotectors.

The invention extends to the pharmaceutical compositions containing atleast one of the medicaments as defined above as active ingredient.

These pharmaceutical compositions can be administered by buccal, rectalroute, by parenteral route or by local route as a topical application onthe skin and mucous membranes or by injection by intravenous orintramuscular route.

These compositions can be solid or liquid and be presented in all thepharmaceutical forms commonly used in human medicine, such as, forexample, plain or sugar-coated tablets, capsules, granules,suppositories, injectable preparations, ointments, creams, gels andaerosol preparations; they are prepared according to the usual methods.The active ingredient can be incorporated with excipients usuallyemployed in these pharmaceutical compositions, such as talc, gum arabic,lactose, starch, magnesium stearate, cocoa butter, aqueous ornon-aqueous vehicles, fatty substances of animal or vegetable origin,paraffin derivatives, glycols, various wetting, dispersing oremulsifying agents, preservatives.

The usual dose, variable according to the product used, the patientbeing treated and the illness in question, can be, for example, 1 to 300mg per day for an adult, by oral route or 1 to 100 mg per day byintravenous route.

Certain starting products of formulae (II) and (XVI) are known and canbe prepared for example as indicated in the European Patent EP 168,950.

Other starting products of formulae (II) and (XVI) can in particular beprepared as indicated in the European Patent EP 0465368, or also in theexamples described hereafter in the experimental part.

Certain starting products of formulae (II) and (XVI) are commercialproducts such as for example, the following products of formula (II):

2-propylimidazole, 2-isopropylimidazole, 2-ethylimidazole,2-methylimidazole.

Examples of commercial products of formula (XVI) are given in patents EP0465368 or EP 0503162.

In particular certain products of formulae (II) and (XVI) can also beprepared from the products of formula (II) for example by subjectingthem to one or more of the reactions described above in a) to r),carried out under the conditions also described above.

Certain products of formula (XVI) can also be obtained by themonohalogenation of the product of formula (II) as defined above intothe product of formula (P₁): ##STR34## in which R'₁ and P have themeanings indicated above for the product of formula (II), which productof formula (P₁) can be reacted, after exchange according to the halogenmetal reaction known to a man skilled in the art, with the appropriateelectrophile, according to the methods known to a man skilled in the artand in particular for example following the same type of reactiondescribed above for passing for example from the compound of formula(IX) to the compound of formula (XI).

Certain products of formula (XVI) can also be prepared according to thefollowing diagram: ##STR35##

Certain products of formula (XVI) can also be prepared according to thefollowing diagram: ##STR36##

Certain products of formula (XVI) can also be prepared according to thefollowing diagram: ##STR37##

The starting compounds of formula (VI) such as 2,4,5-tribromoimidazoleor also the starting products of formulae (XX) and (XXI) may becommercially available or can be prepared according to the usual methodsknown to a man skilled in the art.

The starting products of formula (X) are commercial products such as inparticular:

methyl chloroformate

benzyl chloroformate

isobutyl chloroformate

ethyl chloroformate

N-propyl chloroformate

The starting products of formulae (VIIIa) and (VIIIb) are commercialproducts such as in particular:

the following products of formula (VIIIa):

benzaldehyde or butanal

the following products of formula (VIIIb):

benzoyl or butyryl chloride.

A preparation process for some of the products of formula (III) is inparticular described in the European Patent EP 0465368.

Examples of the preparation of the compounds of formula (III) are alsodescribed in the literature and examples of them are given in particularin the U.S. Pat. No. 4,880,804 or for example in the reference Chemistryand Industry 7 September 1987 HOWARD and COLQUHOUN pp. 612-617.

In particular, the product of formula (III) which is 6-chloro piperonylchloride is commercially available from ACROS.

Finally a subject of the present invention is as new industrialproducts, the compounds of formulae (IV), (V), (IX), (XI) and (XIII) inwhich, it being understood that in the compounds of formulae (IX) and(XI), W represents the CH₂ --Y' radical, Y' represents the phenylradical substituted by a dioxol radical and optionally substituted byanother substituent chosen from halogen atoms and alkoxy and alkylradicals containing at most 4 carbon atoms and in which the ptionalreactive functions are optionally protected by protective groups.

Thus a particular subject of the invention is the use of the products offormula (I) as defined above, for the preparation of pharmaceuticalcompositions intended for the treatment of illnesses resulting from anabnormal stimulation of the endothelin receptors and in particularintended for the treatment of hypertension induced by endothelin, of allvascular spasms, in the treatment of the after-effects of a cerebralhaemorrhage, renal insufficiencies, myocardial infarction, cardiacinsufficiency and in the prevention of the recurrence ofpost-angioplastic stenosis as well of cardiac and vascular fibroses.

The following examples illustrate the invention without however limitingit.

PREPARATION 1 Ethyl 4-bromo-cyclohexaneacetate

STAGE 1: ethyl 2-(4-bromocyclohexylidene)-ethyl acetate

8.07 g of triethylphosphonoacetate is introduced into 20 ml oftetrahydrofuran, the mixture is cooled down to 0° C. and 40 ml of amolar solution of lithium hexamethyldisilazane in tetrahydrofuran isadded. After 15 minutes 6.5 g of 4-bromo-cyclohexanone (prepared asdescribed in Heterocycles, Vol. 18, 1982 p. 163-167) is added and thewhole is left for 1 hour at ambient temperature, followed by hydrolysiswith a saturated solution of ammonium chloride, extraction with ethylacetate, and after chromatography 8.5 g of the expected product(colourless oil) is obtained.

STAGE 2: ethyl 4-bromo-cyclohexaneacetate

3 g of the product obtained in Stage 1 above is introduced into 100 mlof ethanol, the whole is hydrogenated in the presence of platinum oxideas catalyst in order to produce after filtration 2.9 g of expectedproduct (colourless oil).

EXAMPLE 1 ethyl 1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-4-[[4-(2-ethoxy-2-oxoethyl) cyclohexyl]thio]-2-propyl-1H-imidazole-5-carboxylate

STAGE 1: ethyl cyano-[(1-oxobutyl) amino] acetate

5 g of ethyl (hydroxyimino) cyanoacetate, 40 cm³ of etrahydrofuran, 11.5cm³ of butyric anhydride and 2.5 g of platinum are mixed together andthe mixture is agitated under a hydrogen atmosphere until saturation isachieved. After filtering and rinsing with 5×15 cm³ of ethyl ether, theether is evaporated off, 200 cm³ of essence G is added little by little,followed by separating, washing with 3×10 cm³ of essence G and drying atapproximately 75° C. Concentration is carried out to ˜10 cm³, 50 cm³ ofessence G is added, the whole is left to crystallize for 30 mn atambient temperature, followed by separation, washing with 3×3 cm³ ofessence G and drying at approximately 75° C. 5.73 g of product isobtained. M.P.=110° C. Recrystallization for analyses:

540 mg of the product obtained is dissolved in 50 cm³ of isopropyl etherunder reflux, the solution is filtered, concentrated, left forapproximately 1 hour at rest at ambient temperature, followed byseparating, washing with isopropyl ether and drying. 440 mg of expectedproduct is obtained. M.P.=110° C.

Microanalysis for C₉ H₁₄ N₂ O₃ =198.22

    ______________________________________                                                C         H      N          O                                         ______________________________________                                        % calculated                                                                            54.53       7.12   14.13    24.22                                     % found 54.5   7.2  14.0                                                    ______________________________________                                        IR Spectrum CHCl.sub.3                                                        ______________________________________                                              =C--NH        ˜3430 cm.sup.-1                                       -C≅N ˜2245 cm.sup.-1                                          C=O  1758 cm.sup.-1 ester                                                       1692 cm.sup.-1 amide                                                        Amide II  1492 cm.sup.-1                                                    ______________________________________                                    

Stage 2: ethyl 3-amino 2-[(1-oxobutyl) amino] 3-(methylthio)2-propenoate

1.4 ml of triethylamine is added to a solution of 20 g of the nitrileobtained in Stage A above in 400 ml of ethanol, the reaction medium iscooled down to approximately -10° C. and approximately 22 g ofmethylmercaptan is introduced by bubbling it through. Agitation iscarried out for approximately 72 hours at 0° C. The excess methanethiolis eliminated, the ethanol is driven off, followed by impasting inessence G, filtering and drying. 24.3 g of expected product (colourlesscrystals) is obtained. M.P._(K115) =120-124° C. Microanalysis for C₁₀H₁₈ N₂ O₃ S=246.33

    ______________________________________                                                C       H      N         S    O                                       ______________________________________                                        % calculated                                                                            48.76     7.37   11.37   13.02                                                                              19.49                                   % found 48.6   7.5  11.4  12.6  --                                          ______________________________________                                        IR Spectrum CHCl.sub.3                                                          =C--NH.sub.2 3500, 3412 cm.sup.-1                                             =C--NH 3365, 3275 cm.sup.-1                                                   C=O complex 1665 cm.sup.-1                                                    C=C and NH.sub.2 def. 1592 cm.sup.-1                                          Amide II 1488 cm.sup.-1                                                       UV Spectrum in EtOH                                                           Max. 220 nm ε = 5500                                                  Max. 291-292 ε = 19400                                              ______________________________________                                    

Stage 3: ethyl 4-(methylthio) 2-propyl 1H-imidazole 5-carboxylate

A solution of 12.9 g of 4-dimethylaminopyridine in 90 cm³ of methylenechloride is added to 20.1 g of phosphorus pentachloride in 300 cm³ ofmethylene chloride, cooled down to approximately -70° C.

The reaction medium is further maintained for approximately 15 mn atapproximately -70° C. then a solution of 12 g of the product obtained inStage B above in 120 cm³ of methylene chloride is introduced. The wholeis left to return at ambient temperature and is maintained underagitation for approximately 22 hours.

The reaction mixture is poured into 2.5 litres of water+ice andneutralized by the addition of approximately 60 g of sodium bicarbonate.Agitation is carried out again for approximately 30 minutes, followed bydecanting and extraction with 500 cm³ of methylene chloride. Afterwashing with salt water and drying, the solvent is driven off atapproximately 50° C. Purification is carried out by chromatography onsilica eluting with methylene chloride-ethyl acetate (90-10) thenmethylene chloride-ethyl acetate (80-20). The solvents are driven off atapproximately 50° C., followed by impasting with essence G, filteringand drying. 7.4 g of expected product (colourless crystals) is obtained.M.P._(K95) =85° C. Microanalysis Concordance for C₁₀ H₁₆ N₂ O₂ S=228.32

    ______________________________________                                                C       H      N         S    O                                       ______________________________________                                        % calculated                                                                            52.61     7.06   12.27   14.04                                                                              14.02                                   % found 52.7   7.3  12.2  14.0                                              ______________________________________                                        IR Spectrum CHCl.sub.3                                                          =C--NH  3440-3260 cm.sup.-1                                                   C=O complex max. ˜1672 cm.sup.-1                                        Heterocycle  1542-1498 cm.sup.-1                                              UV Spectrum in EtOH                                                           Max. 213-214 nm ε = 14500                                             Infl. 229 nm ε = 7200                                                 Max. 286 nm ε = 12200                                                 UV Spectrum in EtOH/HCl N/10                                                  Max. 238 nm ε = 6800                                                  Max. 277 nm ε = 9600                                                  return to base → max. 296 nm.                                        ______________________________________                                    

STAGE 4: ethyl 1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-4-(methylthio)-2-propyl-1H-imidazole-5-carboxylate

10 g of the product obtained in Stage 3 above and 13.5 g of 6-chloropiperonyl chloride are introduced into 100 ml of dimethyl formamide, 9 gof potassium carbonate is added and the whole is heated to 100° C. forone hour. The reaction medium is cooled down to ambient temperature,then poured onto ice, the precipitate obtained is filtered out thenimpasted in isopropyl ether. In this way 9.25 g of expected product isobtained.

STAGE 5: ethyl 1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-4-(methylsulphinyl)-2-propyl-1H-imidazole-5-carboxylate

9.26 g of the product obtained in Stage 4 above is introduced into 400ml of methylene chloride at 0° C. and 5.8 g of metachloroperbenzoic acidis added. Agitation is carried out for one hour at ambient temperatureand the reaction medium is washed with sodium and potassium hydride,followed by extraction with methylene chloride, washing with water,drying and evaporating the solvent. After chromatography 8.8 g ofexpected product is obtained. M.p.=187° C.

STAGE 6: ethyl 1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-4-mercapto-2-propyl-1H-imidazole-5-carboxylate

800 mg of the product obtained in Stage 5 above is introduced into 16 mlof methylene chloride and 0.54 ml of trifluoroacetic anhydride is added.Agitation is carried out for 30 minutes, followed by evaporating todryness and the residue is taken up in 10 ml of methanol and 4 ml oftriethylamine. Agitation is carried out for 30 minutes, followed byextraction with chloroform, washing with a saturated solution ofammonium chloride, drying and evaporating to dryness. In this way 720 mgof expected product is obtained.

STAGE 7: ethyl 1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-4-[[4-(2-ethoxy-2-oxoethyl) cyclohexyl]thio]-2-propyl-1H-imidazole-5-carboxylate

1 g of the product obtained in Stage 6 above is introduced intodimethylformamide, 146 mg of a suspension of sodium hydride at 60% inoil is added and the reaction medium is left under agitation for 15minutes at ambient temperature. Then 1.08 mg of the product obtained inStage 2 of Preparation 1 is added, and the reaction medium is left underagitation for 24 hours at ambient temperature, followed by hydrolysiswith a saturated solution of ammonium chloride and extraction with ethylacetate. In this way, after chromatography, 1.1 g of expected product(amorphous solid) is obtained.

EXAMPLE 2 4-((4-(carboxymethyl) cyclohexyl)thio)-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2-propyl-1H-imidazole-5-carboxylic acid

760 mg of the product of Example 1 is introduced into 20 ml oftetrahydrofuran, 50 ml of ethanol and 25 ml of 2N soda are added and thewhole is left for 24 hours at ambient temperature. The tetrahydrofuranand the ethanol are evaporated off then the reaction medium is acidifiedto pH 1. After extraction with ethyl acetate and evaporating to dryness,the residue is recrystallized from ethanol. 490 mg of expected productis obtained. M.p.=166° C.

EXAMPLE 3 4-((5-(carboxypentyl) thio)-1-((6-chloro 1,3-benzodioxol-5-yl)methyl)-2-(1,3-dioxolan-2-yl)-1H-imidazole-5-carboxylic acid

STAGE 1:1-((6-chloro-1,3-benzodioxol-5-yl)-methyl)-2,4,5-tribromo-1H-imidazole

25 g of 2,4,5-tribromoimidazole is introduced into 500 ml ofdimethylformamide and 4.3 g of sodium hydride is added. Agitation ismaintained for 10 minutes at ambient temperature. Next 18.4 g of6-chloro piperonyl chloride, then 25 g of sodium iodide are added to thereaction medium and agitation is continued for 15 minutes at ambienttemperature.

The reaction medium is finally poured into 3 litres of water, separated,washed abundantly with water, then successively with 250 ml of ethanol,250 ml of isopropanol, then finally with 250 ml of isopropyl ether.

After drying, 31.5 g of expected product (cream solid) is collectedM.p.=225° C. IR CHCl₃ (cm⁻¹) Absence of ═C--NH

    ______________________________________                                        Aromatic heterocycle                                                                             1624-1506-1497-1485                                        ______________________________________                                    

STAGE 2:4,5-dibromo-1-[(6-chloro-1,3-benzodioxol-5-yl)-methyl]-1h-imidazole-2-carboxaldehyde

20 g of the product obtained in Stage 1 above is introduced into 200 mlof anhydrous methylene chloride to which 500 ml of anhydrous ethyl etheris added. A 3M solution of ethyl magnesium bromide in ethyl ether isadded and the whole is left under agitation for 20 minutes at ambienttemperature. Then an excess (15 ml) of anhydrous dimethylformamide isadded. After 2 hours at ambient temperature, hydrolysis is carried outwith 200 ml of 1N hydrochloric acid followed by extraction 3 times with300 ml of ethyl acetate. The organic phase is washed with saturatedsodium chloride then dried and evaporated to dryness. In this way 14.5 gof expected product is obtained.

STAGE 3: 4,5-dibromo-1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-2-(1,3-dioxolan-2yl)-1H-imidazole

The product obtained in Stage 2 above is introduced into 200 ml oftoluene, 20 ml of ethylene glycol is added and the reaction medium istaken to reflux overnight then evaporated to dryness. 200 ml of asaturated solution of sodium hydrogen carbonate is added which isextracted 3 times with 200 ml of ethyl acetate. The organic phase iswashed with saturated sodium chloride, then dried and evaporated todryness. The residue obtained is impasted in isopropyl ether, filteredand dried. In this way 13.5 g of expected product (solid) is obtained.M.p.=188° C.

STAGE 4: 4-bromo-1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-2-(1,3-dioxolan-2-yl)-1H-imidazole-5-carboxaldehyde

10 g of the product obtained in Stage 3 above is introduced into 200 mlof anhydrous tetrahydrofuran. 10 ml of ethyl magnesium bromide (3Msolution in ethyl ether) is added and the reaction medium is left underagitation for 20 minutes at ambient temperature. Then an excess ofanhydrous dimethylformamide is added. After 2 hours at ambienttemperature, hydrolysis is carried out with 200 ml of 1N hydrochloricacid and extraction is carried out 3 times with 300 ml of ethyl acetate.The organic phase is washed with saturated sodium chloride then driedand evaporated to dryness. The residue obtained is impasted in isopropylether. In this way 7.6 g of expected product is obtained, which is usedwithout purification for the following stage.

STAGE 5: ethyl 6-[[1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-2-(1,3-dioxolan-2-yl)-5-formyl-1H-imidazol-4-yl]thio]-hexanoate

3.9 g of ethyl 6-mercaptohexanoate is dissolved in 200 ml of anhydrousdimethylformamide, 1.1 g of sodium hydride at 50% in oil is added andthe reaction medium is left for 20 minutes at ambient temperature. Then7.6 g of the product obtained in Stage 4 above is added, and the wholeis left overnight at ambient temperature. The dimethyl-formamide isevaporated off under vacuum, the residue is taken up in 200 ml ofsaturated ammonium chloride and extraction is carried out with threetimes 200 ml of methylene chloride. The organic phases are dried,filtered and evaporated to dryness. The residue is impasted in isopropylether and filtered. In this way 5.8 g of expected product (solid) isobtained.

STAGE 6: 4-((5-(carboxypentyl) thio) 1-((6-chloro 1,3-benzodioxol-5-yl)methyl) 2-(1,3-dioxolan-2-yl)-1H-imidazole-5-carboxylic acid

5.1 g of the product obtained in Stage 5 above is introduced into 100 mlof methylene chloride, 500 ml of methanol is added then by fractions: 22g of manganese oxide, 2.2 g of sodium cyanide and 1.5 ml of acetic acidare added. The reaction medium is left under agitation for 72 hours atambient temperature, then filtered and washed with methylene chloride.The organic phase is washed with saturated sodium chloride then driedand evaporated to dryness. The residue obtained is chromatographed onsilica to give 3.1 g of intermediate methyl ester which is saponified ina mixture of 2N soda/ethanol to give 2.5 g of expected product.M.p.=175° C.

EXAMPLE 4 4-((5-(carboxypentyl) thio) 1-((6-chloro 1,3-benzodioxol-5-yl)methyl) 2-(methoxymethyl)-1H-imidazole-5-carboxylic acid

STAGE 1: 4,5-dibromo-1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-2-(methoxymethyl)-1H-imidazole

28.2 g of the product obtained in Stage 1 of Example 3 is introducedinto 400 ml of ethanol, 2.5 g of sodium borohydride is added and after 2hours, 10 ml of acetic acid is added. Agitation is carried out for 15minutes, followed by evaporating to dryness, the residue is impasted inisopropyl ether, filtered and 27.5 g of a cream solid is obtained. The27.5 g obtained previously is dissolved in 400 ml of tetrahydrofuran,3.73 g of sodium hydride at 50% in oil is added, agitation is carriedout for 15 minutes and 4.5 ml of methyl iodide is added. The reactionmedium is left overnight at ambient temperature, extracted with ethylacetate and after chromatography, 18.7 g of expected product isobtained.

STAGE 2: 4-((5-(carboxypentyl) thio)-1-((6-chloro 1,3-benzodioxol-5-yl)methyl) 2-(methoxymethyl)-1H-imidazole-5-carboxylic acid

The operation is carried out as in Stages 4, 5 and 6 of Example 3starting with the product obtained in Stage 1 above and in this way theexpected product is obtained. M.p.=170° C.

EXAMPLE 5 ethyl 1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-4-[(6-ethoxy-6-oxohexyl)thio]-2-propyl-1H-imidazole-5-carboxylate

The operation is carried out as in Stage 7 of Example 1 starting withthe product obtained in Stage 6 of Example 1 and ethyl 6-bromo-hexanoateinstead of ethyl 4-bromocyclohexaneacetate.

In this way the expected product is obtained.

EXAMPLE 6 4-((5-(carboxypentyl) thio) 1-((6-chloro 1,3-benzodioxol-5-yl)methyl)-2-propyl-1H-imidazole-5-carboxylic acid

The operation is carried out as in Example 2 starting with the productof Example 5 and in this way the expected product is obtained. M.p.=145°C.

EXAMPLE 7 ethyl 1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-4-[(5-ethoxy-5-oxopentyl)thio]-2-propyl-1H-imidazole-5-carboxylate

The operation is carried out as in Stage 7 of Example 1 starting withthe product obtained in Stage 6 of Example 1 and ethyl5-bromo-pentanoate instead of ethyl 4-bromocyclohexaneacetate. In thisway the expected product is obtained.

EXAMPLE 8 4-((4-carboxybutyl) thio)-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2-(propyl)-1H-imidazole-5-carboxylic acid

The operation is carried out as in Example 2 starting with the productof Example 7 and in this way the expected product is obtained. M.p.=156°C.

EXAMPLE 9 ethyl 1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-4-[[4-(2-ethoxy-2-oxoethylidene) cyclohexyl]thio]-2-propyl-1H-imidazole-5-carboxylate

1.1 g of the product obtained in Stage 6 of Example 1 is introduced, 127mg of a suspension of sodium hydride at 50% in oil is added and thereaction medium is left under agitation for 15 minutes at ambienttemperature. Then 657 mg of the product obtained in Stage 1 ofPreparation 1 is added and the reaction medium is left under agitationfor 24 hours at ambient temperature, followed by hydrolysis with asaturated solution of ammonium chloride and extraction with ethylacetate and after chromatography, 880 mg of the expected product(amorphous solid) is obtained.

EXAMPLE 10 4-((4-(carboxymethylene) cyclohexyl) thio)-1-((6-chloro1,3-benzodioxol-5-yl) methyl)-2-propyl-1H-imidazole-5-carboxylic acid

880 mg of the product of Example 9 is introduced into 20 ml oftetrahydrofuran, 50 ml of ethanol and 25 ml of 2N soda are added and thereaction medium is left for 24 hours at ambient temperature. Thetetrahydrofuran and the ethanol are evaporated off, then the reactionmedium is acidified to pH 1. Extraction is carried out with ethylacetate, followed by evaporation to dryness and the residue isrecrystallized from ethyl acetate. In this way 490 mg of expectedproduct is obtained. M.p.=168° C.

EXAMPLE 11 ethyl 2-butyl-1-[(6-chloro-1,3-benzodioxol-5-yl)-methyl]-4[(6-ethoxy-6-oxohexyl) thio]-1H-imidazole-5-carboxylate

The operation is carried out as in Example 1, using in Stage 4 ofExample 1 ethyl 2-n-butyl-4-(methylthio)-1H-imidazole-5-carboxylateobtained as indicated in Stage d) of Example 56 of EP 0503162 instead ofethyl 2-n-propyl-4-(methylthio)-1H-imidazole-5-carboxylate and using inStage 7 of Example 1 ethyl 6-bromohexanoate instead of ethyl4-bromocyclohexaneacetate. In this way the expected product is obtainedin the form of a yellow oil.

EXAMPLE 12 2-butyl 4-((5-carboxypentyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl)-1H-imidazole-5-carboxylic acid

The operation is carried out as in Example 2 starting with the productof Example 11. In this way the expected product is obtained. M.p. 128°C.

By operating as in Stage 7 of Example 1 and Example 2, starting withethyl 1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 4-mercapto 2-propyl1H-imidazole 5-carboxylate obtained as indicated in Example 1 Stage 6and the appropriate halogenated or tosylated derivative, the products ofthe following examples were prepared:

EXAMPLE 13 1-((6-chloro 1,3-benzodioxol-5-yl) methyl)4-((4-carboxycyclohexyl) thio) 2-propyl 1H-imidazole 5-carboxylic acid(cis/trans). M.p.=174° C. EXAMPLE 14 4-(((4-carboxycyclohexyl) methyl)thio) 1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole5-carboxylic acid (cis/trans). M.p.=184° C. EXAMPLE 154-(((3-carboxycyclohexyl) methyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole 5-carboxylic acid(diastereoisomers). M.p.=178° C. EXAMPLE 16 cis 4-(((2-((carboxymethoxy)methyl) cyclohexyl) methyl) thio) 1-((6-chloro 1,3-benzodioxol-5-yl)methyl) 2-propyl 1H-imidazole 5-carboxylic acid (diastereoisomers).M.p.=172° C. Preparation of the Reagents Used at the Start of Examples13 to 16.

1) Preparation of ethyl 4-bromo cyclohexyl carboxylate used at the startof Example 13.

0.9 ml of phosphorus tribromide is introduced slowly into 5 ml of ethyl(4-hydroxycyclohexyl) carboxylate and the reaction medium is heated at80° C. for 6 hours. The whole is left to return to ambient temperature,followed by washing with salt water, extraction with ethyl acetate,drying and evaporating the solvent under reduced pressure. The residueis chromatographed on silica (eluant: AcOEt-cyclohexane 10-90) and 3.51g of expected product is obtained.

2) Preparation of ethyl 1-((4-tosyloxymethyl) cyclohexyl) arboxylateused at the start of Example 14.

1 g of 1,4-dihydroxymethyl cyclohexane in 10 ml of dimethylformamide isagitated for 5 hours at ambient temperature in the presence of 0.94 g ofimidazole and 1.8 ml of diphenyl trimethyl silane chloride then thewhole is poured into a saturated aqueous solution of ammonium chloride,followed by extraction with ethyl acetate, washing with salt water anddrying, the solvent is evaporated off under reduced pressure, theresidue is chromatographed on silica (eluant: CH₂ Cl₂ -AcOEt 95-5). 1.31g of silylated derivative is obtained. 13.06 g of silylated derivativeprepared as indicated above in 260 ml of dimethylformamide is agitatedfor 40 hours at ambient temperature with 45 g of pyridinium dichromate,then partially concentrated under reduced pressure, the reaction mediumis poured into 400 ml of ice-cooled hydrochloric acid (N), extractedwith ethyl acetate, followed by washing with a solution of sodiumbicarbonate, drying, the solvent is evaporated off under reducedpressure and 13.1 g of crude acid is obtained. 12.53 g of the acidobtained above in 125 ml of 1000 ethanol is agitated for 70 hours atambient temperature in the presence of 10 ml of chlorotrimethylsilanethen the solvents are evaporated off under reduced pressure. Afterchromatography on silica (eluant CH₂ Cl₂ -AcOEt 95-5 to 80-20), 3.40 gof unblocked ester is obtained. Formation of the tosylate.

3.40 g of the preceding derivative in 10 ml of pyridine is cooled downto 0°/+5° C., 5.22 g of tosyl chloride in 25 ml of dichloromethane isadded over 50 minutes and agitation is carried out for 20 hours atambient temperature. The reaction medium is poured into 200 ml of Nhydrochloric acid, followed by extraction with dichloromethane, washingwith water and drying, the solvent is evaporated off under reducedpressure, the residue is chromatographed on silica (eluant:cyclohexane/AcOEt 2-8) and 5.50 g of expected tosylate is obtained

3) Preparation of ethyl 1-((3-tosyloxymethyl) cyclohexyl) carboxylateused at the start of Example 15.

Formation of the Acid Chloride

5 g of 1,3-cyclohexane dicarboxylic acid in 10 ml of thionyl chloride isagitated for 3 hours under reflux, the excess reagent is distilled off,the residue is taken up in toluene, the solvent is evaporated off and6.04 g of expected product is collected.

Formation of the Ester

1.69 ml of ethanol and 50 ml of tetrahydrofuran are cooled down to 0°C., 18.12 ml of n-butyllithium in solution in tetrahydrofuran (1.6 M/l)is added over 30 minutes and agitation is carried out for 30 minutes at0°/+5° C. This solution is added over 30 minutes to 6.04 g of the acidchloride obtained previously in 60 ml of tetrahydrofuran at atemperature below 10° C.

Reduction into the Alcohol

While maintaining this temperature, 58 ml of lithiumtri(terbutoxyalumino hydride) is added over 30 minutes, agitation iscarried out for 1 hour, the reaction medium is poured into Nhydrochloric acid, followed by extraction with ethyl acetate, washingwith salt water, drying and evaporating under reduced pressure, theresidue is chromatographed (eluant: CH₂ Cl₂ /AcOEt 9-1) and 1.37 g ofthe alcohol is obtained.

Formation of the Tosylate

1.33 g of the preceding alcohol in 5 ml of pyridine is cooled down to0°/+5° C., 1.63 g of tosyl chloride in 5 ml of dichloromethane is addedover 20 minutes and agitation is carried out for 20 hours at ambienttemperature. The reaction medium is poured into 100 ml of N hydrochloricacid, followed by extraction with ethyl acetate, washing with water anddrying, the solvent is evaporated off under reduced pressure, theresidue is chromatographed on silica (eluant: CH₂ Cl₂) and 1.97 g ofexpected tosylate is obtained.

4) Preparation of ethyl 1-((2-tosyloxymethyl) cyclohexyl) carboxylateused at the start of Example 16.

Formation of the Ester

2.23 ml of ethyl diazoacetate in solution in 16 ml of dichloromethane isadded over 1 hour at ambient temperature to 3.06 g of cis1,2-cyclohexane dimethanol in 100 ml of dichloromethane in the presenceof a few drops of ethyl etherate borotrifluoride. The reaction medium ismaintained under agitation for 16 hours at ambient temperature, followedby washing with water and drying, the solvent is evaporated off underreduced pressure, the residue is chromatographed on silica (eluant:AcOEt/cyclohexane 20-80) and 1.98 g of expected product is obtained.

Formation of the Tosylate

1.01 g of the preceding product in 5 ml of pyridine is cooled down to0°/+5° C., 1.00 g of tosyl chloride in 5 ml of dichloromethane is addedover 30 minutes and agitation is carried out for 16 hours at ambienttemperature. The reaction medium is poured into 100 ml of N hydrochloricacid, followed by extraction with dichloromethane, washing with waterand drying, the solvent is evaporated off under reduced pressure, theresidue is chromatographed on silica (eluant: cyclohexane/AcOEt 2-8) and1.38 g of expected tosylate is obtained.

EXAMPLE 17 trans 4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-(1,3-dioxolan-2-yl) 1H-imidazole5-carboxylic acid.

Stage A: ethyl amino (cyano) acetate.

20 g of ethyl cyano (hydroxyimino) acetate is suspended in 200 ml ofwater. A saturated solution of sodium bicarbonate prepared with 16 g ofNaHCO₃ and 160 ml of water is added over 15 minutes at ambienttemperature. The reaction medium is heated to 35° C., 68 g of sodiumdithionite is added, over 15 minutes, the whole is left to return toambient temperature. The medium is saturated with NaCl. After extractionwith 5 times 500 ml of CH₂ Cl₂ the organic phases are dried andconcentrated under reduced pressure and 12.75 g of expected product isobtained.

Stage B: ethyl ((acetyloxyacetyl) amino) cyano acetate.

24.3 g of acetoxyacetyl chloride in solution in 60 ml of tetrahydrofuranis added to 23 g of the product obtained as in Stage A in 10 ml oftetrahydrofuran in the presence of 10 ml of pyridine. Agitation iscarried out at ambient temperature for 4 hours, the solvent isevaporated off, the residue is taken up in ethyl acetate, followed bywashing with salt water and drying, the solvent is evaporated off underreduced pressure, the residue is crystallized form ethyl ether and 27.59g of expected product is obtained. M.p.=82° C.

Stage C: ethyl 3-((2-((acetyloxyacetyl) amino) 3-(amino(4-methoxyphenyl) methyl) thio) 2-propenoate.

33.4 ml of 4-methoxy benzyl mercaptan is added dropwise to 27.59 g ofthe product obtained in Stage B in solution in 500 ml of ethanol and inthe presence 5 ml of triethylamine. Agitation is carried out for 16hours at ambient temperature, the solvent is evaporated off underreduced pressure, followed by crystallization from ethyl ether,separation and drying under reduced pressure. 33.7 g of expected productis obtained. M.p.=145° C.

Stage D: ethyl 2-((acetyloxy) methyl) 5-(((4-methoxyphenyl) methyl)thio) 1H-imidazole 4-carboxylate.

2.3 g of the product obtained in Stage C in 50 ml of ethyl acetate isheated under reflux, 3.16 ml of propane 1-phosphonic anhydride at 50% inethyl acetate is added, agitation is carried out for 30 minutes, thewhole is left to cool down and neutralized with a saturated aqueoussolution of sodium bicarbonate. Extraction is carried out with ethylacetate, followed by washing with salt water and drying, the solvent isevaporated off and after impasting in ether and drying, 2.09 g ofexpected product is obtained. M.p.=126° C.

Stage E: ethyl 2-(hydroxymethyl) 5-(((4-methoxyphenyl) methyl) thio)1H-imidazole 4-carboxylate.

26 g of the product obtained as in Stage D in 600 ml of ethanol isheated under reflux for 5 days in the presence of 1.3 g of paratoluenesulphonic acid. The solvent is evaporated off under reduced pressure,the residue is taken up in ethanol and 6 g of expected product isobtained. After concentration of the mothers liquors and chromatographyon silica (eluant: AcOEt-cyclohexane 5-5), 9.44 g of additional expectedproduct is collected.

Stage F: ethyl 2-formyl 5-(((4-methoxyphenyl) methyl) thio) 1H-imidazole4-carboxylate. 8.6 g of the product obtained in Stage 6 in 300 ml ofdichloromethane and 100 ml of methanol is agitated for 1 hour at ambienttemperature in the presence of 43 g of manganese. After filtering, thesolvent of the solution obtained is evaporated off under reducedpressure and 6 g of expected product is obtained which is used as it isfor the following stage.

Stage G: ethyl 1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 2-formyl4-(((4-methoxyphenyl) methyl) thio) 1H-imidazole 5- carboxylate.

3 g of the product obtained in Stage F in 150 ml of dimethylformamide isagitated at ambient temperature for 50 hours with 2.58 g of potassiumcarbonate and 2.87 g of 6-chloropiperonyl chloride. Another 1.5 g ofchlorinated reagent is added and agitation is carried out for 48 hours.The solvent is evaporated off under reduced pressure, the residue istaken up in 150 ml of a saturated aqueous solution of ammonium chloride,followed by extraction with ethyl acetate, washing with salt water anddrying, the solvent is evaporated off, the residue is chromatographed onsilica (eluant: AcOEt-cyclohexane 2-8) and after impasting in isopropylether 3.71 g of expected product is obtained.

Stage H: mercury bis ((1-((6-chloro 1,3-benzodioxol-5-yl) methyl)2-formyl 5-ethoxycarbonyl 1H-imidazol-4-yl) thiolate).

A suspension containing 2.6 g of the product obtained as in Stage G in2.6 ml of anisole and 13 ml of trifluoroacetic acid is cooled down to 0°C. 1.13 g of mercury trifluoro-acetate is added, the reaction medium isleft to return to ambient temperature, agitation is carried out for 2hours, the solvent is evaporated off under reduced pressure, the residueis taken up in ethanol, the mercury salt obtained is separated anddried. 1.83 g of expected product is collected.

Stage I: mercury bis ((1-((6-chloro 1,3-benzodioxol-5-yl) methyl)2-(1,3-dioxolan-2-yl) 5-ethoxycarbonyl 1H-imidazol-4-yl) thiolate).

500 mg of the product obtained in Stage H in 100 ml of toluene is heatedunder reflux with 165 mg of ethylene glycol and 25 mg of paratoluenesulphonic acid, while eliminating the water formed. The solvent isevaporated off under reduced pressure, the crystals formed are separatedand dried. After concentration of the mothers liquors and impasting inethyl ether, the additional crystallized product is separated and dried.540 mg of expected product is obtained. M.p.=186 C.

Stage J: ethyl 1-((6-chloro 1,3-benzodioxol-5-yl) methyl)2-(1,3-dioxolan-2-yl) 4-mercapto 1H-imidazole 5-carboxylate.

A current of hydrogen sulphide is bubbled for 10 minutes through amixture containing 530 mg of the product obtained in Stage I in 100 mlof ethyl acetate, followed by filtering, washing with ethyl acetate,concentrating under reduced pressure and 500 mg of expected product isobtained which is used as it is for the following stage.

Stage K: ethyl trans 1-((6-chloro 1,3-benzodioxol-5-yl) methyl)2-(1,3-dioxolan-2-yl) 4-(4-(((ethoxycarbonyl) methyl) cyclohexyl) thio)1H-imidazole 5-carboxylate.

60 mg of sodium hydride at 50% in oil is added to 500 mg of the productobtained in Stage J in solution in 20 ml of N, N-dimethylformamide,agitation is carried out for 15 minutes, 610 mg of ethyl 4-iodocyclohexane acetate is added and the reaction medium is maintained underagitation for 16 hours. 50 ml of a saturated aqueous solution ofammonium chloride is added, extraction is carried out withdichloromethane, the organic phase is washed with salt water, thesolvent is evaporated off under reduced pressure and the residue ischromatographed on silica (eluant: AcOEt-cyclohexane 3-7). 380 mg ofexpected product is obtained.

Stage L: trans 4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-(1,3-dioxolan-2-yl) 1H-imidazole5-carboxylic acid.

380 mg of the product obtained in Stage K, 20 ml of 2N soda and 20 ml ofethanol are mixed together, tetrahydrofuran is added until dissolutionis obtained and the reaction medium is maintained under agitation atambient temperature for 2 days. The solvent is evaporated off underreduced pressure, the residue is taken up in water, acidified to pH=1with 2N hydrochloric acid, followed by filtering, washing with water,drying under reduced pressure at 60° C. and 280 mg of expected productis collected. M.p.=171° C. Preparation of ethyl 4-iodo cyclohexaneacetate used in Stage K of Example 17.

Stage a: trans 4-iodo cyclohexanol.

44 g of 7-oxabicyclo [2.2.1] heptane is poured dropwise into 250 ml of57% hydroiodic acid while maintaining the reaction medium at ambienttemperature and under agitation for 4 hours. The reaction medium ispoured into ice-cooled water and extracted with ethyl ether, theethereal phases are washed with 200 ml of 0.5N sodium thiosulphate,washed with salt water, dried and the solvents are evaporated off. 96.47g of expected product is obtained. M.p.=53.4° C.

Stage b: 4-iodo cyclohexanone.

52.4 g of potassium permanganate is added to 50 g of the productobtained in Stage a) in solution in 500 ml of acetonitrile. Agitation iscarried out for 16 hours at ambient temperature, followed by filtering,the solvent is evaporated off under reduced pressure, the residue ischromatographed on silica (eluant: AcOEt-cyclohexane 20-80) and 36.17 gof expected product is obtained. M.p.=48.7° C.

Stage c: ethyl 4-iodo cyclohexylidene acetate.

6.6 g of sodium hydride at 60% in oil then 36.04 g of the productobtained in Stage b) dissolved in 100 ml of tetrahydrofuran are addedslowly to a mixture containing 32 ml of triethylphosphonoacetate in 200ml of tetrahydrofuran. The reaction medium is maintained under agitationat ambient temperature, two lots of 2 g of sodium hydride are added thenthe reaction medium is poured into water and neutralized by the additionof 150 ml of a saturated aqueous solution of ammonium chloride.Extraction is carried out with ethyl acetate, followed by washing withsalt water and drying, the solvents are evaporated off under reducedpressure, purification is carried out by chromatography on silica(eluant: AcOEt-cyclohexane 3-7) and 38.25 g of expected product isobtained.

Stage d: ethyl 4-iodo cyclohexane acetate.

A mixture containing 38.25 g of the product obtained in Stage c), 300 mlof tetrahydrofuran and 1.5 g of platinum oxide then 5 g of platinum at5% on activated charcoal is hydrogenated under 600 mbars of pressure for48 hours. After filtering, the solvent is evaporated off under reducedpressure, the residue is chromatographed on silica (eluantAcOEt-cyclohexane 10-90) and 27.01 g of expected product is obtained.

By operating as in Example 17 omitting Stages E, F and I, using at thestart the product obtained in Example 17 Stage A and the appropriateacid chloride, the following products were prepared:

EXAMPLE 18 trans 4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-(2-furanyl) 1H-imidazole 5-carboxylicacid. M.p.=185° C. EXAMPLE 19 trans 4-((4-(carboxymethyl) cyclohexyl)thio) 1-((6(-chloro 1,3-benzodioxol-5-yl) methyl) 2-cyclopentyl1H-imidazole 5-carboxylic acid. M.p.=171° C. EXAMPLE 20 trans3-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-(2-thienyl) 1H-imidazole 5-carboxylicacid. M.p.=195° C. EXAMPLE 21 trans (3-((4-(carboxymethyl) cyclohexyl)thio) 1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 2-cyclohexyl1H-imidazole 5-carboxylic acid. M.p.=165° C.

The operation is carried out as in Example 17 using ethyl 4-bromocyclohexyl carboxylate as in Example 13 instead of the iodatedderivative in order to obtain the product of Example 22.

EXAMPLE 22 4-((4-(carboxycyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl 2-(2-furanyl) 1H-imidazole 5-carboxylicacid (cis/trans). M.p.=165° C. EXAMPLE 23 Disodium salt of4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole 5-carboxylic acid(cis).

1 g of 4-((4-(carboxymethyl) cyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole 5-carboxylic acidprepared as in Example 10 is recrystallized from ethanol and 780 mg ofthe pure cis derivative is collected which is dissolved in 31.51 ml of0.1N soda. The solvents are evaporated off under reduced pressure and949 mg of the expected cis sodium disalt is collected. M.p.=166° C.

EXAMPLE 24 Dipotassium salt of 4-((4-(carboxymethyl) cyclohexyl) thio)1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole5-carboxylic acid.

The operation is carried out as indicated in Example 23 replacing the0.1N soda with 0.1N potash. The expected potassium disalt is obtained.M.p. >250° C.

EXAMPLE 29 Pharmaceutical Composition

Tablets were prepared corresponding to the following formula:

Product of Example 2 . . . 50 mg Excipient for a tablet made up to . . .200 mg (detail of excipient: lactose, talc, starch, magnesium stearate).

PHARMACOLOGICAL RESULTS

1) Study of the Affinity for the Endothelin a Receptor

A membrane preparation is prepared from the heart (ventricles) of a rat.The tissue is ground up in a POLYTRON in a 50 mM Tris buffer pH=7.4.

After 30 minutes at 25° C. (W.B.) the homogenate is centrifuged at30,000 g for 15 minutes (2 centrifugations with intermediate take-up inthe Tris buffer pH 7.4).

The pellets are suspended in an incubation buffer (25 mM Tris, 5microg/ml pepstatin A, 3 microg/ml aprotinin, 0.1 mM PMSF, 3 mM EDTA, 1mM EGTA pH 7.4).

2 ml aliquoted fractions are distributed in hemolysis tubes and ¹²⁵ Iendothelin (approx. 5,000 dpm/tube) and the product to be studied areadded. (The product is first tested at 3×10 5M three times). When thetested product displaces more than 50% of the radioactivity specificallybound to the receptor, it is tested again according to a range of 7concentrations in order to determine the concentration which inhibits by50% the radioactivity specifically bound to the receptor. In this waythe 50% inhibitory concentration is determined.

The non-specific bond is determined by the addition of endothelin at10⁻⁶ M (three times). After incubation at 25° C. for 60 minutes,replacing in a water bath at 0° C. for 5 minutes, filtration underreduced pressure and rinsing with Tris buffer pH 7.4, the radioactivityis counted in the presence of scintillating Triton.

The result is expressed directly as the 50% inhibitory concentration(IC₅₀), that is to say as the concentration of product studied,expressed in nM, necessary to displace 50% of the specific radioactivityfixed to the receptor studied.

Result:

The IC₅₀ 's found for the products of the examples are given in Table 1hereafter, in nanomoles.

                  TABLE I                                                         ______________________________________                                                       Endothelin A receptor                                            Product of examples IC.sub.50 in nanomoles                                  ______________________________________                                        2              1.1                                                              6 1.2                                                                         8 1.9                                                                         10  1.2                                                                       12  1.1                                                                     ______________________________________                                    

2) Study of the Affinity for the Endothelin B Receptor

A membrane preparation is prepared from the rear cortex plus thecerebellum of a rat. The tissue is ground up in a POLYTRON in a 50 mMTris buffer pH=7.4.

After 30 minutes at 25° C. (W.B.) the homogenate is centrifuged at30,000 g for 15 minutes (2 centrifugations with intermediate take-up inthe Tris buffer pH 7.4).

The pellets are suspended in an incubation buffer (25 mM Tris, 5microg/ml pepstatin A, 3 microg/ml aprotinin, 0.1 mM PMSF, 3 mM EDTA, 1mM EGTA pH 7.4).

2 ml aliquoted fractions are distributed in hemolysis tubes and ¹²⁵ Iendothelin (approx. 5,000 dpm/tube) and the product to be studied areadded. (The product is first tested at 3×10⁻⁵ M three times). When thetested product displaces more than 50% of the radioactivity specificallybound to the receptor, it is tested again according to a range of 7concentrations in order to determine the concentration which inhibits by50% the radioactivity specifically bound to the receptor. In this waythe 50% inhibitory concentration is determined.

The non-specific bond is determined by the addition of endothelin at10⁻⁶ M (three times). After incubation at 25° C. for 60 minutes,replacing in a water bath at 0° C. for 5 minutes, filtration underreduced pressure and rinsing with Tris buffer pH 7.4, the radioactivityis counted in the presence of scintillating Triton.

The result is expressed directly as the 50% inhibitory concentration(IC₅₀), that is to say as the concentration of product studied,expressed in nM, necessary to displace 50% of the specific radioactivityfixed to the receptor studied.

Results:

The IC₅₀ 's found for the products of the examples are given in Table Ihereafter, in nanomoles.

                  TABLE I                                                         ______________________________________                                                       Endothelin B receptor                                            Product of examples IC.sub.50 in nanomoles                                  ______________________________________                                        2              194                                                              6 293                                                                         8 600                                                                         10  210                                                                     ______________________________________                                    

3) Test for Antagonistic Activity of Endothelin in the Demedullated Rat

Male Sprague Dawley rats (250 to 350 g) are anaesthetized (sodiumpentobarbital 60 mg/kg injected by intraperitoneal route). The animal isplaced under assisted respiration and a bilateral section of the vagusnerves is carried out. The rat is then demedullated.

The average arterial pressure is recorded with a heparin catheter (PE50)introduced into the carotid of the animal, and connected via a pressuresensor and an amplifier to a recorder (Gould, Pressure Processor). Acatheter is introduced into the pudendal vein in order to allowinjection of the molecules to be studied. After a stabilization period(about 15 minutes), the product or the solvent is injected 10 minutesbefore a range of increasing doses of endothelin which are injectedevery 2 minutes (0.1-0.3-1-3-10 μg/kg).

The anatagonistic activity of the products is estimated by thepercentage inhibition in the increase in pressure induced by theendothelin at doses of 3 and 10 μg/kg.

    ______________________________________                                        Results                                                                                                 % inhibition of vasoconstriction                    EXAMPLES  Doses mg/kg ET.sub.1 μg/kg                                                                        ET.sub.1 μg/kg                            ______________________________________                                        2         0.3         -56        -39                                             1.0 -60 -65                                                                   3.0 -63 -77                                                                  3 1.0 -52 -53                                                                  3.0 -64 -71                                                                  4 10.0  -49 -38                                                               6 1.0 -42 -33                                                                  3.0 -49 -37                                                                  8 1.0 -40 -22                                                                  3.0 -57 -47                                                                  10  1.0 -59 -39                                                                3.0 -58 -61                                                                  12  10.0  -30 -35                                                           ______________________________________                                    

4) Revealing the Antagonistic Activity of Endothelin, on the IsolatedAorta of a Rat

The thoracic aorta is removed from Wistar male rats (approximately 350g) (IFFA CREDO France) anaesthetized with pentobarbital (60 mg/kg IP)then exsanguinated. The aorta is rapidly put into a physiologicalsolution at ambient temperature. A 1 to 2 mm ring without endothelium isput in an isolated organ bath containing 5 ml of the followingphysiological solution (composition in mM NaCl: 118.4; KCl: 4.7; MgSO₄,7H₂ O: 1.2; CaCl₂, 2H₂ O: 2.5; KH₂ PO₄ : 1.2; NaHCO₃ : 25; glucose:10.1) the medium is maintained at 37° C. and oxygenated with a mixtureof oxygen (95%) carbon dioxide (5%). The initial pressure imposed is 2g, the rings are left at rest for 60 to 90 minutes. The referencecontraction is caused by the addition of 2 successive concentrations of3 μM of noradrenalin, left in contact for 15 minutes, followed by 3washings, the second response serves as the reference contraction. Afterreturn to the base line, incubation is carried out for 15 minutes with aconcentration of the product to be tested or the solvent then cumulativeconcentrations of endothelin are added every 5 minutes (concentrationsof 1 to 1000 μM). The inhibition induced by the product is calculated asa % of the reduction relative to the reactivity of the control curvesover 2 points: concentration of 10 and 30 nM of endothelin.

    ______________________________________                                        Results                                                                                     Concentration                                                      of antagonist % inhibition of contraction                                  EXAMPLES  μM        ET 10 Nm  ET 30 nM                                     ______________________________________                                        2         0.1          -71       -61                                             1.0 -94 -100                                                                 6 0.1 -96 -99                                                                  1.0 -96 -98                                                                  8 0.1 -97 -97                                                                  1.0 -95 -96                                                                  12  0.1 -88 -65                                                                1.0 -98 -98                                                                ______________________________________                                    

5) Protection Against Sudden Death Induced by IV Injection of Endothelin(ET1) in a Female Mouse

A lethal dose of ET1 (10 nmole/kg IV) is injected into female mice. Thesolvent or the molecules to be studied are injected 10 minutes before(i.v. route) or 30 minutes before (oral route) the endothelin.

The protection is calculated in the form of ED₅₀ (50% effective dose, orthe dose capable of reducing the mortality by 50% relative to thecontrol group).

    ______________________________________                                        Results                                                                                            ED.sub.50 mg/kg                                          EXAMPLES         IV     PO                                                    ______________________________________                                        2                0.8    1.1                                                     3 5.0 24.1                                                                    6 3.9 NT                                                                      8 3.5 NT                                                                      10  3.3 3.2                                                                 ______________________________________                                         NT means "not tested                                                     

We claim:
 1. A compound selected from the group consisting of allpossible racemic, enantiomeric and diastereoisomeric isomer forms of acompound of the formula ##STR38## wherein R₁ is selected from the groupconsisting of a) alkyl of 1 to 6 carbon atoms unsubstituted orsubstituted with at least one hydroxy or alkoxy of 1 to 6 carbon atomsand b) saturated or unsaturated cycloalkyl of 3 to 7 ring membersselected from the group consisting of carbon, oxygen, nitrogen andsulfur, R₂ and R₃ are individually an acid or acid isoteric group, Y isphenyl substituted with dioxol and optionally substituted with a memberselected from the group consisting of halogen and alkyl and alkoxy of 1to 4 carbon atoms and its salts with non-toxic, pharmaceuticallyacceptable acids or bases.
 2. A compound of claim 1 wherein R₂ and R₃are individually selected from the group consisting of free carboxy,salified carboxy, carboxy esterified with an alcohol of up to 6 carbonatoms, tetrazolyl and salified tetrazolyl.
 3. A compound of claim 1wherein R₁ is selected from the group consisting of a) alkyl of 1 to 6carbon atoms unsubstituted or substituted with at least one hydroxy oralkoxy of 1 to 6 carbon atoms, b) cycloalkyl of 3 to 6 carbon atomsoptionally containing one or two ring members selected from the groupconsisting of oxygen, nitrogen and sulfur and c) thienyl or furyl, R₂ is--(CH₂)_(n) --S--A, n is an integer from 0 to 4, A is a) alkyl of 1 to10 carbon atoms substituted with a member selected from the groupconsisting of free carboxy, salified carboxy, carboxy esterified with analcohol of up to 6 carbon atoms, tetrazolyl and salified tetrazolyl, andb) cycloalkyl of 5 to 6 ring members optionally containing 1 or 2 oxygenor nitrogen ring members and optionally substituted by a member selectedfrom,the group consisting of free carboxy, salified carboxy, carboxyesterif ied with an alcohol of up to 6 carbon atoms, tetrazolyl,salified tetrazolyl and alkyl, alkenyl, alkoxy and alkylthio of up to 6carbon atoms optionally interrupted by oxygen or sulfur and optionallysubstituted with a member selected from the group consisting of carboxy,salified carboxy, esterified carboxy, tetrazolyl and salified tetrazolyland R₃ is selected from the group consisting of free carboxy, salifiedcarboxy, carboxy esterified with an alcohol of up to 6 carbon atoms,tetrazolyl and salified tetrazolyl.
 4. A compound of claim 1 wherein R₁is selected from the group consisting of methoxy methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, cyclopentyl,cyclohexyl, dioxolane, dioxane, dithiolane, thienyl and furyl, R₂ isselected from the group consisting of a) alkylthio of 3 to 10 carbonatoms substituted with a member selected from the group consisting offree carboxy, salified carboxy, carboxy esterified with an alcohol of upto 6 carbon atoms, tetrazolyl and salified tetrazolyl, cyclohexylthiooptionally substituted by carboxy or by alkoxy itself optionallysubstituted by carboxy and b) cyclohexythio, cyclopentylthio andpiperidinylthio substituted with a member selected from the groupconsisting of free carboxy, salified carboxy, carboxy esterified with analcohol of up to 6 carbon atoms, tetrazolyl, salified tetrazolyl andalkyl, alkenyl, alkoxy and alkylthio of up to 4 carbon atoms substitutedby a member selected from the group consisting of free carboxy, salifiedcarboxy, esterified carboxy, tetrazolyl, salified tetrazolyl, R₃ isselected from the group consisting of free carboxy, salified carboxy,carboxy esterified with an alcohol of up to 6 carbon atoms, tetrazolyland salified tetrazolyl and Y is phenyl substituted with dioxol andoptionally by halogen.
 5. A compound of claim 1 wherein R₁, is selectedfrom the group consisting of methoxy methyl, n-propyl, isopropyl,N-butyl, isobutyl, tert.-butyl and dioxolane, R₂ is selected from thegroup consisting of a) alkylthio of 3 to 5 carbon atoms substituted witha member selected from the group consisting of free carboxy, salifiedcarboxy and carboxy esterified with an alcohol of up to 6 carbon atoms,and b) cyclohexylthio substituted with a member selected from the groupconsisting of free carboxy, salified carboxy, carboxy esterif ied withan alcohol of up to 6 carbon atoms and alkyl and alkenyl of up to 4carbon atoms substituted with a member selected from the groupconsisting of free carboxy, salified carboxy and carboxy esterified withan alcohol of up to 6 carbon atoms, R₃ is selected from the groupconsisting of free carboxy, salified carboxy and carboxy esterified withan alcohol of up to 6 carbon atoms and Y is phenyl substituted withdioxol and halogen.
 6. A compound of claim 1 selected from the groupconsisting of4-((4-(carboxymethylene) cyclohexyl)thio)-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2-propyl-1H-imidazole-5-carboxylic acid, 4-((5-carboxypentyl)thio)-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2-(1,3-dioxolan-2-yl)-1H-imidazole-5-carboxylic acid,4-((4-(carboxymethyl) cyclohexyl)thio)-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2-propyl-1H-imidazole-5-carboxylic acid, 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 4-((4-carboxy-cyclohexyl) thio) 2-propyl1H-imidazole 5-carboxylic acid, 4-(((4-carboxycyclohexyl) methyl) thio)1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole5-carboxylic acid, cis 4-(((2-((carboxymethoxy) methyl) cyclohexyl)methyl) thio) 1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 2-propyl1H-imidazole 5-carboxylic acid, trans 4-((4-(carboxymethyl) cyclohexyl)thio) 1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 2-(1,3-dioxolan-2-yl)1H-imidazole 5-carboxylic acid, 4-((4-(carboxymethyl) cyclohexyl) thio)1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 2-(2-furanyl) 1H-imidazole5-carboxylic acid, trans 4-((4-(carboxymethyl) cyclohexyl) thio)1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 2-cyclopentyl 1H-imidazole5-carboxylic acid, trans 3-((4-(carboxymethyl) cyclohexyl) thio)1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 2-(2-thienyl) 1H-imidazole5-carboxylic acid, 4-((4-carboxycyclohexyl) thio) 1-((6-chloro1,3-benzodioxol-5-yl) methyl) 2-(2-furanyl) 1H-imidazole 5-carboxylicacid, disodium salt of 4-((4-(carboxymethyl) cyclohexyl) thio)1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole5-carboxylic acid, dipotassium salt of 4-((4-(carboxymethyl) cyclohexyl)thio) 1-((6-chloro 1,3-benzodioxol-5-yl) methyl) 2-propyl 1H-imidazole5-carboxylic acid.
 7. A method of treatment of illness from an abnormalstimulation of endothelin receptors in warm-blooded animals comprisingadministering to such warm-blooded animals an effective amount of acompound of claim 1 sufficient to treat illnesses due to an abnormalstimulation of endothelin receptors.